Modulation of voltage-dependent facilitation of the T-type calcium current by sodium ion in isolated frog atrial cells

Abstract

Sodium ions have been reported to alter the permeation properties of L- and N-type Ca2+ channels. Here in frog atrial cardiomyocytes under whole-cell patch-clamp conditions, we have examined the effects of lowering the external Na+ concentration on the amplitude of T-type Ca2+ current, ICaT, and on the relief of its steady-state inactivation by large depolarizing prepulses, ICaT facilitation. A partial reduction in Na+ ion concentration did not significantly alter ICaT amplitude elicited at -50 mV. However, after a large depolarization, low- Na+ solutions enhanced the relief of inactivation and induced ICaT facilitation. This facilitation occurred independently of the divalent charge carrier, high intracellular Ca2+ buffering or the intracellular Na+ content. Its effects were additional to the beta-adrenergic effects mediated by a decrease of Gi/o-protein inhibitory tone. In Ca2+-free solution the very large T-type current, then carried by Na+ ions, showed only a weak relief of inactivation. In conclusion, ICaT facilitation--which, as previously reported, is modulated by the transient voltage-dependent relief of Gi-protein inhibitory tone--is further enhanced in a low-Na+ solution. In Ca2+-free solution, relief of inactivation due to re-openings dependent on the divalent charge carrier is improbable. It thus appears that for a short while after a large depolarization, external Na+ compete with Ca2+ ions on permeation-controlling sites, so as to modulate channel re-openings and thus the amplitude of voltage-facilitated ICaT independently of the control exerted by the inhibitory G-protein.

Extracellular Ca2+ Modulates the Effects of Protons on Gating and Conduction Properties of the T-type Ca2+ Channel α1G (CaV3.1)

“…The effects of pH e were most pronounced in the absence of extracellular Ca 2+ (5 mM EDTA). Under these conditions, T-type Ca 2+ channels, like HVA Ca 2+ channels, conduct large currents of monovalent cations ( Carbone and Lux, 1987 ; Talavera et al, 1998 ; Alvarez et al, 2000 ). Fig.…”

“…Both gating and permeation mechanisms of voltage-dependent Ca 2+ channels are modulated by ionic conditions and particularly by extracellular protons and Ca 2+ ( Prod'hom et al, 1989 ; Tytgat et al, 1990 ; Shuba et al, 1991 ; Kwan and Kass, 1993 ; Chen et al, 1996 ; Polo-Parada and Korn, 1997 ; Alvarez et al, 2000 ; Delisle and Satin, 2000 ; Shah et al, 2001 ). For T-type Ca 2+ channels in particular it has been shown previously that extracellular protons shift the voltage dependence of channel activation due to neutralization of surface charges and decrease the voltage sensitivity of channel activation, which is not consistent with the surface charge hypothesis ( Tytgat et al, 1990 ; Delisle and Satin, 2000 ; Shah et al, 2001 ).…”

“… Shuba et al (1991) showed that the mean open time of the T-type channel of mouse neuroblastoma cells depends on the type and concentration of the permeant ion and proposed that the channel region controlling channel closure senses a smaller fraction of the electric field due to a dynamic interaction between the ionic flux and the selectivity filter. In frog-atrial cardiomyocytes, Alvarez et al (2000) showed that channel reopening after strong depolarizing prepulses was enhanced in low-Na + extracellular solutions and proposed that a competition between Na + and Ca 2+ for binding sites within the channel modulates the amplitude of the voltage-facilitated T-type current. It is also known that the α 1G clone (Ca V 3.1) shows faster macroscopic inactivation in the presence of Ba 2+ than in Ca 2+ ( Klugbauer et al, 1999 ; Staes et al, 2001 ).…”

Splice-variant changes of the CaV3.2 T-type calcium channel mediate voltage-dependent facilitation and associate with cardiac hypertrophy and development

“…Of note, native I Ca,T from bullfrog atrial cells and guinea-pig coronary arterial myocytes have both been reported to display VDF properties. [48][49][50] Conversely, Zhong and coworkers reported faster recovery kinetics associated with the homologous exon 26 region in the human fetal brain Ca V 3.2 channel although neither facilitation nor potentiation (>100% fractional recovery) were observed. 35 VDF has been previously attributed to the cloned human Ca V 3.3 40,41 albeit to a much lower degree (∼20%) compared to that for the Ca V 3.2(-25) variant channel described here ( Fig.…”

Paradoxical Potentiation of Neuronal T-Type Ca2+Current by ATP at Resting Membrane Potential

“…The kinetics of this regulation is similar to that in thalamocortical neurons reported here, but the potentiation requires a strong depolarizing prepulse (more than Ϫ30 mV) and is not modified by the omission of ATP. In isolated bullfrog atrial cells, strong depolarizations (Ͼ0 mV) relieve a G i -protein-mediated inhibition of T-channel activity (Alvarez et al, 1996(Alvarez et al, , 2000, inducing a short-duration facilitation. Similarly, depolarizations larger than Ϫ30 mV can relieve a tonic current inhibition mediated by tyrosine kinases in mouse spermatogenic cells (Arnoult et al, 1998).…”